Alzheimer's Disease (AD) is characterized by the presence of intraneuronal tangles and extracellular amyloid plaques, which are accompanied by neurodegeneration and cognitive impairment. The major goal of this Program Project is to develop animal models that are useful not only for the understanding of the molecular and neural mechanisms of neuronal degeneration and impaired learning and memory in AD, but which are also amenable to the development of effective strategies for gene therapy of AD. Project 2 focuses on the roles of nerve growth factor (NGF), the neurotrophin receptor p75, and acetylcholine (ACh) within central cholinergic systems in learning and memory. NGF, p75m, and choline acetyltransferase (ChAT)(the biosynthetic enzyme) for ACh), conditional mutant mice established by the Cre-LoxP system will be injected with viral vectors expressing Cre into specific regions of adult brain to remove these molecules. Furthermore, mutations in the gene encoding the amyloid precursor protein (APP) have been discovered in familial AD patients, implicating APP in the etiology of AD. Several lines of in vitro evidence suggest that neurotrophins and p75 might modify the expressing, processing, or functions of APP or the aggregation of its processed products, including beta-amyloid. Conversely, APP and its processed products may influence neurotrophin signaling. NGF and p75 mutant mice will e crossed with transgenic mice expressing mutated human APP that display neuroanatomical alterations resembling AD. Time-course of neuroanatomical alterations and behavioral deficits will be determined in these compound mice. The aims are: Aim 1. To determine the role of p75, nerve growth factor (NGF) and acetylcholine (ACh) in the survival and function of adult basal forebrain cholinergic neurons (BFCNs). Aim 2. To determine the role of p75 and NGF in the neurotoxicity of beta-amyloid in adult BFCNs.